1. Field of the Invention
The present invention relates generally to the fields of implantable ocular devices, pharmaceutics, and methods of drug delivery to the eye. More particularly, it concerns implantable ocular devices for the sustained delivery of a therapeutic compound to the eye.
2. Description of Related Art
Glaucoma is the leading cause of blindness worldwide. It is the most common cause of optic neuropathy.
One major risk factor for developing glaucoma is family history. Several different inherited forms of glaucoma have been described. Primary congenital or infantile glaucoma is an inherited disorder that is characterized by an improper development of the aqueous outflow system of the eye, which leads to elevated intraocular pressure and damage to the optic nerve.
Open angle glaucoma is a common disorder characterized by atrophy of the optic nerve resulting in visual field loss and eventual blindness. Open angle glaucoma has been divided into two major groups, based on age of onset and differences in clinical presentation. Juvenile-onset open angle glaucoma (JOAG) usually manifests itself in late childhood or early adulthood. Adult- or late-onset primary open angle glaucoma (POAG) is the most common type of glaucoma. It is milder and develops more gradually than JOAG, with variable onset usually after the age of 40. POAG is associated with slight to moderate elevation of intraocular pressure, and often responds satisfactorily to regularly monitored medical treatment. Unfortunately, this disease may not be detected until after irreversible damage to the optic nerve has already occurred because it progresses gradually and painlessly.
Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are considered to be at high risk for the eventual development of the visual loss associated with glaucoma. If glaucoma or ocular hypertension is detected early and treated promptly with medications that effectively reduce elevated intraocular pressure, loss of visual function or its progressive deterioration can generally be ameliorated. Drug therapies that have proven useful for the reduction of intraocular pressure include both agents that decrease aqueous humor production and agents that increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally.
Examples of agents used for treating glaucoma include β-blockers (e.g., timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol), carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), α1 antagonists (e.g., nipradolol), α2 agonists (e.g. iopidine and brimonidine), miotics (e.g., pilocarpine and epinephrine), prostaglandin analogs (e.g., latanoprost, travoprost, unoprostone, and compounds set forth in U.S. Pat. Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151,444), “hypotensive lipids” (e.g., bimatoprost and compounds set forth in U.S. Pat. No. 5,352,708), and neuroprotectants (e.g., compounds from U.S. Pat. No. 4,690,931, particularly eliprodil and R-eliprodil, as set forth in a pending application U.S. Ser. No. 60/203,350, and appropriate compounds from WO 94/13275, including memantine.
One of the limitations of topical therapy is inadequate and irregular delivery of the therapeutic agent to the eye. For example, when an eye drop is applied to the eye, a substantial portion of the drop may be lost due to overflow of the lid margin onto the cheek.
Various ocular drug delivery implants have been described in an effort to improve and prolong drug delivery. For example, U.S. Pat. No. 3,949,750 discloses a punctal plug made of a tissue-tolerable, readily sterilizable material, such as Teflon, HEMA, hydrophilic polymer, methyl methacrylate, silicone, stainless steel or other inert metal material. It is stated that the punctal plug may be impregnated with ophthalmic medication or that the punctal plug may contain a reservoir of the ophthalmic drug.
U.S. Pat. No. 5,053,030 discloses an intracanalicular implant that can be used as a carrier or medium for distributing medications throughout the body. U.S. Pat. No. 5,469,867 discloses a method of blocking a channel, such as the lacrimal canaliculus by injecting a heated flowable polymer into the channel and allowing it to cool and solidify. The polymer may be combined with a biologically active substance that could leach out of the solid occluder once it has formed in the channel.
WO 99/37260 discloses a punctal plug made of a moisture absorbing material, which is not soluble in water, such as a modified HEMA. It is also disclosed that an inflammation inhibitor, such as heparin, may be added to the material from which the punctal plug is made.
U.S. Pat. No. 6,196,993 discloses a punctal plug containing glaucoma medication. The medication is contained in a reservoir within the plug. The reservoir is in fluid communication with a pore through which the medication is released onto the eye.
U.S. Pub. No. 2003/0143280 discloses the use of biodegradable polymer capsules fro treating ophthalmic disorder including dry eye and glaucoma. The capsules are made of any biodegradable, biocompatible polymer and may contain a treating agent.
U.S. Pub. No. 2004/0013704 discloses solid or semi-solid implant compositions lacking polymeric ingredients. These implant compositions are made of lipophilic compounds and may be implanted anywhere in the eye including the punctum or lacrimal canaliculous. It is stated that the implants may contain any ophthalmic drug, including anti-glaucoma drugs.
WO 2004/066980 discloses a device for delivering a carbonic anhydrase inhibitor (CAI) to the eye over an extended period of time. In one embodiment, the device has an inner CAI-containing core and an outer polymeric layer. The outer layer may be permeable, semi-permeable, or impermeable to the drug. Where the outer layer is impermeable to the drug, it may have one or more openings to permit diffusion of the CAI.
U.S. Pub. No. 2005/0232972 discloses ocular implants to which active agents have been applied to at least one surface. In one embodiment, the implant may contain a hollow core filled with medication. In another embodiment, the medication may be applied to one or more bands of polymer material. Alternatively, a porous or absorbent material can be used to make up the entire plug or implant which can be saturated with the active agent.
WO 2006/031658 discloses lacrimal canalicular inserts including a polymer component and a therapeutic component. The polymer component may include one or more non-biodegradable polymers, one or more biodegradable polymers, or combinations thereof. The insert may comprise a matrix of a polymer component and a therapeutic component. The inserts may be coated with a substantially impermeable coating.
U.S. Pub. No. 2006/0020248 discloses an ophthalmological device for lacrimal insertion that includes a reservoir for a medication, such as a glaucoma, antimicrobial, anti-inflammatory, or dry-eye syndrome medication.
A reservoir drug-delivery device is a device that contains a receptacle or chamber for storing the drug. There are drawbacks to reservoir drug delivery devices in that they are difficult to manufacture, difficult to achieve drug content uniformity (i.e., device to device reproducibility, particularly with small ocular devices), and they carry the risk of a “dose dump” if they are punctured. In matrix drug delivery devices the drug is dispersed throughout a polymeric matrix and is released as it dissolves or diffuses out of the matrix. Matrix devices have an advantage over reservoir devices in that they are not subject to a dose dump if punctured. A disadvantage of matrix devices is that it can be difficult to achieve zero-order drug release kinetics. Zero-order drug release or near zero-order drug release is desirable because the rate of drug release is independent of the initial concentration of the drug, thus the drug can be released at therapeutic levels over a sustained period of time. The manufacture of matrix devices can also present difficulties when the drug and the polymer are processed and extruded at elevated temperature and/or pressure as this may reduce the activity of the drug.
The devices of the present invention address these deficiencies in the art by providing matrix devices that achieve zero-order or near zero-order drug-release kinetics typically associated with reservoir devices, but without the risk of dose dumping and the manufacturing difficulties of reservoir devices.